Dipeptidyl peptidase IV (DPP-IV) inhibitors have recently attracted much attention as a treatment for diabetes (especially type II diabetes) and numerous derivatives have been reported as DPP-IV inhibitors. Of these derivatives, aminoacetyl pyrrolidine carbonitrile derivatives have been shown to exhibit hypoglycemic activity. Several of these compounds are reported to be promising antidiabetic agents (Non-Patent Documents 1 and 2, Patent Documents 1 through 16). The present applicant previously disclosed aminoacetyl pyrrolidine carbonitrile derivatives represented by the following structural formula (4):
(Chemical Formula 1)
(wherein X is CH2, CHF or CF2; R3 is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a tetrahydropyranyl group, a substituted or unsubstituted arylmethyl group, a substituted or unsubstituted arylethyl group, a substituted or unsubstituted aromatic hydrocarbon, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted aliphatic heterocyclic ring; and n is 1 or 2.) (Patent Document 9)
The derivatives of the formula (4) are produced by reacting a 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile derivative or a 1-(2-bromoacetyl)pyrrolidine-2-carbonitrile derivative with a corresponding amine in the presence of a base (Patent Document 9). The 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile derivative or the 1-(2-bromoacetyl)pyrrolidine-2-carbonitrile derivative used as the starting material is produced by reacting bromoacetyl chloride or chloroacetyl chloride with a pyrrolidine derivative (Patent Documents 1 through 9).
An alternative synthesis technique that uses neither bromoacetyl chloride nor chloroacetyl chloride is a method via a sulfonyloxyacetyl pyrrolidine derivative. Sulfonyloxyacetyl pyrrolidine derivatives are known as a general idea (Patent Documents 14 through 17). The use of 1-(2-methanesulfonyloxyacetyl)pyrrolidine-2-carbonitrile derivatives or 1-(2-toluenesulfonyloxyacetyl)pyrrolidine-2-carbonitrile derivatives is also described (Patent Documents 10 through 13). However, none of these articles specifically describes techniques for producing sulfonyloxyacetyl pyrrolidine derivatives, or the use or physical and chemical properties of these compounds, nor is it clear whether these disclosures are useful in the production of aminoacetyl pyrrolidine carbonitrile derivatives.    Non-Patent Document 1: Journal of Medicinal Chemistry, Vol. 46, p. 2774 (2003)    Non-Patent Document 2: Bioorganic & Medicinal Chemistry, Vol. 12, p. 6053 (2004)    Patent Document 1: Japanese Translation of PCT International Application No. 2000-511559    Patent Document 2: Japanese Translation of PCT International Application No. 2002-531547    Patent Document 3: Japanese Patent Application Laid-Open No. 2002-356471    Patent Document 4: Japanese Translation of PCT International Application No. 2004-500321    Patent Document 5: Japanese Translation of PCT International Application No. 2005-529078    Patent Document 6: Japanese Translation of PCT International Application No. 2004-503531    Patent Document 7: U.S. 2002/019339    Patent Document 8: WO 04/099185 Pamphlet    Patent Document 9: WO 05/075421 Pamphlet    Patent Document 10: WO 02/38541 Pamphlet    Patent Document 11: WO 03/095425 Pamphlet    Patent Document 12: Japanese Patent Application Laid-Open No. 2004-26820    Patent Document 13: Japanese Patent Application Laid-Open No. 2006-160733    Patent Document 14: Japanese Patent Application Laid-Open No. 2002-356472    Patent Document 15: Japanese Patent Application Laid-Open No. 2004-2367    Patent Document 16: Japanese Patent Application Laid-Open No. 2004-2368    Patent Document 17: WO 04/009544 Pamphlet